Transcript War on Cancer

We are not winning the
‘War on Cancer’
(1) Over 200$ billion spent
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
(2) Combination chemotherapy
can defeat a few cancers (leukemia,
lymphoma,testicular cancer)
(3) Most cancers are not curable, if
found too late; success of new drugs,
other treatments is measured in
terms of delaying death by a few months
WHY ARE WE LOSING? WHAT CAN BE DONE
DIFFERENTLY?
Evolutionary Biology of Cancer
(1) What is cancer?
(2) How does cancer develop?
(3) How does cancer evolve（生长） in the body?
(4) How do cancer risk, and cancer-related
genes, evolve over evolutionary time?
(5) How can evolutionary tools be
used to fight cancer?
The simplest definition is from
the American Cancer Society (ACS).
According to the ACS, cancer is a group
of diseases characterized by uncontrolled
growth and spread of abnormal cells.
If the spread is not controlled, it can result in death
发育异常
malignant
恶性的
dysplasia
Epithelial 上皮的
Mesenchymal 间叶
细胞的
间叶细胞的
Some cancer terminology（术
语）
Classification by tissue type:
• carcinoma（癌科）
•
epithelial cell
90% of all tumours
derived from ectoderm （外胚层）
(mostly) or endoderm（内胚层）
(some)
• sarcoma内瘤
•
connective tissue
2% of all tumours
derived from mesoderm中胚层
• leukaemia白血病
•
Classification by the type of cells:
• Adenomatous腺瘤 cells
ductal 管状or glandular腺状 cells
• Squamous 鳞状cells
flat cells
• Myeloid骨髓
•
blood cell
• Lymphoid
lymphocytes or macrophages巨噬细胞
circulatory or lymphatic
8% of all tumours
derived from mesoderm
Cancer is many diseases with one commonality
Some more
cancer
terminology
Oncogene 致癌
基因
Cadherins 钙粘
素
Apoptosis 细胞
凋亡
Angiogenic 血管
原的
Metastasis 转移
转移
Cancer Cells Evolve
by Natural Selection
• Variation变异 in the population of cells:
–
Somatic mutations.
• Variation amongst cells is Heritable可遗传的:
–
Mutations in DNA, chromosomes,
methylation甲基化 patterns.
• Variation affects Reproduction and Survival
of the cells:
–
e.g., suppression of apoptosis
etc.
Progression
of Cancer
• (1) Mutations in genes related to cell cycle,
tissue growth, invasion, apoptosis, cellular
senescence衰老, cell adhesion, angiogenesis
血管再生
• (2) Genetic (chromosomal and microsatellite)
instability
• (3) Clonal growth, somatic mutation and
selection (usually need 5+ mutations)
The Hallmarks特点 of Cancer,
all of which evolve somatically
•
•
•
•
•
•
•
(1) self-sufficiency in growth signals
(2) insensitivity to anti-growth signals
(3) evading apoptosis
(4) sustained angiogenesis
(5) limitless replicative potential
(6) invasion and metastasis
(7) escaping immunosurveillance
Where do such abilities come from, genetically and developmentally?
关联
Placental胎盘
Trophoblast滋
养层
Other sources of cancer cell ‘adaptations’
刺激性伤害
胃肠管道
Telomerase 端粒酶 Gastrointestinal胃肠的
Cancer cells evolve via genetic changes
in large numbers of genes, via many pathways
一种信号通路
基因突变
P53 肿瘤抑制基因 诱导细胞凋 癌症
亡
Evolution Within a Neoplasm
neutral
neutral
Frequency
within
the
Neoplasm
瘤
neutral
neutral
p53p16+/-
p16-/-
CANCER
p53BE
HGD
Time
How Does Diversity 多样性Change During
Progression? Genetic and Demographic种群统
计 Change
Lineages
世系
Number
of Clones
Divergence
扩散
No Selective
Waves of Clonal
Population
Expansion
Subdivisions细分 Sweeps清除
胃肠基质
瘤
Oncogenetic trees
(phylogenetic种群基因的 trees
inferredusing genetic variation in
cancer cells) can help elucidate阐明
genetic pathways to cancer
CGH 比较基因组杂交
杂合蛋白
抑制物
‘Cancer Genes’: genes that evolve mainly in
selective contexts环境 other than cancer, but whose
somatic mutation contributes to cancer development
• Tumor suppressor: gene who product can
cause apoptosis (suicide) or cellular
senescence 衰老(quiescence) in cells gone bad
(gatekeepers) (eg.TP53) (loss of function), or
favor good DNA repair (caretakers)(eg BRCA1)
• Proto-oncogene: genes that can mutate such
that its protein product induces cancer (to an
oncogene)
• Oncogene: gene whose protein product
induces cancer (gain of function)
TP53 LOH (loss of one parental copy)
Predicts Progression to Cancer
RR = 16, 95% CI: 6.2 – 39
Reid et al., Am. J. Gastro. 2001; 96:2839-48
遗传毒
性显现
Stem cells are
a key cause of
Carcinogenesis
癌症发生
because they are
naturally
immortal (until
individual dies)
结构限制
Early and current
models of
carcinogenesis
表型多
样性
种系
寄生
随机
漂变
取样
捕食
等位基因
激素
Population Genetics of Cancer:
Rate of Evolution
• What is the probability of a new
cellular/genetic variant 变量emerging and
expanding in a population? Function of:
–
–
–
–
Mutation rate
Population size
Generation time
Strength of selection (rate of clonal
expansion)
Genetic Diversity Predicts Progression
Number of Clones
•
Median:
–
–
•
•
progressors 促进剂
3 (range: 1 - 9)
non-progressors
1 (range: 1 - 7)
RR = 1.40 per clone
(95% CI:1.13 - 1.73)
p < 0.01
Controlling for p53 LOH,
aneuploidy and tetraploidy
非整倍性
四倍性
Maley et al. (2006) Nat.
Gen. 38:468–73
N=267
Genetic Diversity Predicts Progression
Mean Pairwise Divergence偏差
Median:
•
–
–
•
•
progressors
7% (range: 0–54%),
non-progressors
0% (range: 0–27%)
RR = 1.45 per 10%
divergence
(95% CI:1.08 - 1.95)
p < 0.05
Controlling for p53 LOH,
aneuploidy and tetraploidy
Maley et al. (2006) Nat.
Gen. 38:468–73
N=267
食
道
癌
发
生
率
异类的
外显率
暴露
Rationale 基本原理
Indiscriminate 不受
限制的 mutant 突变
种
调节
持续
Plus evolution…..
错误搭配
固有的
易误性
自然选择
Cancer Risk Increases
with Age (~40% get it, in lifetime)
due to
(1) sequential 连续的accumulation
of mutations over a long time
(2) senescence-related
tissue changes
that can promote cancer
development
Cancer risk involves trade-offs平衡: one important form of
evolutionary trade-off is between cancer risk and
senescence via cumulative loss of functioning cells
老化
出现
干细胞停止分裂
萎缩
Judy Campisi,
UC Berkeley
增值停止
体内平衡
矛盾
成本效益（分析）的
Prevailing dogma 流行观点
Paradox
矛盾
Mutagenic 诱导突变的物质
Another
trade-off, this
one involved
in cancer
progression
暗喻
How does cancer risk evolve
(over evolutionary time)?
(1) Selection against cancer risk occurs late in life,
is relatively weak
(2) Selection that increases cancer risk as a
byproduct: ‘cancer’ genes evolve in other contexts,
such as rapid growth, longevity, placentation,胚胎
形成 genomic imprinting印迹, male-female
conflicts; strong selection, rapid evolution may
increase cancer risk as a byproduct
-> Are cancer genes subject to positive selection?
猩猩
zhonglei
推定的
概率值
化学感知
嗅觉
配子形成
精子发生与运动
*
干扰素
感官感知
Why expect positive selection on
cancer genes? (Crespi and Summers 2006)
• Genes subject to rapid evolution, conflicts,
and antagonistic反对的 coevolution are
often involved in control of cellular
proliferation增生 and growth
• Control over cell proliferation is key to
carcinogenesis癌症发生
• Antagonistic coevolution involves strong
positive selection
Genes that are Positively-selected AND Cancer-related:
some known cases
•
•
•
•
Angiogenin血管生成素
SPANX （ct抗原）
Homeobox同源框
BRCA1 and 2
同源框
Angiogenin血管生成素 gene
•
•
•
•
Angiogenin gene - under positive selection among primates critical role in tissue vascularization脉管化 of the developing placenta
胎盘and embryo胚胎, maternal母亲的immune tolerance of the fetus胎儿,
and vascular and tissue homeostasis自我平衡.
Exhibits elevated高效的 expression in many types of tumors, and
ANG antagonists（ANG 阻断剂） inhibit cancer growth
ANG may be subject to the parent-offspring 亲子间conflicts over
resource transfer that are an integral part of placentation 胎盘形成and
pregnancy with cancer as a side effect of the ‘tug-of-war’激烈竞争 over
the levels of placental development.
Invasive入侵的 placentation shares many biochemical and
physiological features with the development of cancer. Test further by
comparing ANG evolution in eutherian真哺乳动物亚纲 mammal
lineages 世系with invasive vs non-invasive placentation
SPANX genes
•
Family of X-linked伴X染色体的, primate-specific cancer/testis 睾丸
associated genes (CTAs), -expression in normal testis, involved in
spermatogenesis精子发生, and melanoma黑素瘤 tumor cells, promote
cancer cell growth. Roles in spermatozoa development and function,
cell cycle regulation, and apoptosis. Associated with aggressiveness
of skin tumors, inherited testicular and prostate前列腺 cancer risk.
•
Strong positive selection on SPANX genes in primates (including
humans). hypothesized 推测SPANX genes may contribute to
spermatozoa fitness. Kleene (2005) provides additional evidence that
CTAs such as SPANX are subject to extremely strong selection in the
context of sperm production rates and numbers. Cancer cells
dedifferentiate去分化 and take on properties of immortal male germ
cells. 呈现不死性
•
>100 genes functionally related to SPANX, clinical promise临床反应 as
targets of cancer immunotherapy 免疫疗法
Homeobox genes
•
Encode 编码transcription factors转录因子 that direct various
crucial developmental processes, such as the patterning of body
plans形态组成, the control of cell growth and the determination of stem
cell fate. Altered homeobox gene expression is found in many
cancers.
•
Pem homeobox gene has been shown to evolve very rapidly in
rodents,啮齿动物under the effects of positive selection. X-linked gene
is expressed in primordial germ cells古细菌 and placental membranes
during embryogenesis胚胎生成, and reproductive tissues (testis and
ovaries) during adulthood; also expressed in tumors, where it
promotes tumor cell growth. Appears to regulate placental
development and the development of sperm and eggs cells in
some manner.
BRCA1 and BRCA2乳腺癌基因
•
The BRCA1 gene is a central component of pathways regulating
the cell cycle, DNA repair, and cell growth and apoptosis - acts as
a tumor suppressor, but it also exhibits crucial functions during
development. Thus, human female BRCA1 heterozygotes 杂合体
exhibit substantially lower weights at birth than homozygotes纯合体,
null无 BRCA1 mice die in early embryogenesis with severe growth
defects, and the gene exhibits its greatest expression in the highlyproliferative terminal end buds of the breast epithelium in pubertal
发育期mice.
•
Positive selection has been inferred in large sample of eutherian
mammals. Also positive selection along the chimp黑猩猩 and human
lineages, and selection is ongoing at this locus in human populations.
BRCA1 and 2: Two Hypotheses
•
BRCA1 interacts with BRCA2, and many alleles等位基因 at both
BRCA1 and BRCA2 are associated with human breast cancer. BRCA2,
which is also thought to be involved in DNA repair and early
development, appears to be subject to sexually antagonistic
selection 基因的性别对抗性选择in humans, in that alleles that
increase female mortality also enhance male viability生存能力.
BRCA1 genotype is known to affect birth weight of its female bearers
•
Reactive breast size is considerably higher in humans than in other
primates, and, indeed, breasts develop prematurely 早熟的(well before
they could be used in lactation哺乳期). This rapid evolutionary
increase in size may have selected for alleles promoting breast
development, which have the pleiotropic多效性 effect of increased
cancer risk. Similar considerations apply to other rapidly-evolved
aspects of human morphology形态学, such as brain size, bone growth,
and prostate前列腺.
Conclusions from known cases
• Multiple genes/gene families with
coincident (1) positive selection, (2)
relation to cancer, (3) evidence for role of
antagonistic coevolution 拮抗进化in
genetic diversification多样性
• HOW MANY MORE? e. g., P53, AR,
prostate-expressed genes, placentallyexpressed genes, etc.
• Find new cancer-related genes this way?
How evolutionary mismatches can affect cancer risk
*
固有失误
暴露
随机性
*
解剖
*
易感性
哺乳期持续时间
三头肌皮肤褶皱
子宫上
皮
子宫内膜
What is the role of evolutionary biology
in cancer research and therapy治疗?
(1) Help to identify diet, life-style risks
(2) Aid in development of therapies that counter, bypass
or exploit evolutionary potential开发进化潜能 of cancer cells
(3) Apply phylogenetic 系统发育学methods to cancer
lineage 系evolution
(4) Analyze molecular-evolution, positive selection of
known or putative 推断的cancer-related genes across
evolutionary time (comparative tests)
CANCER IS AN EVOLUTIONARY PROBLEM AT
TWO LEVELS:
Somatic 机体and Phylogenetic系统发育
Evolution Works Against Our Therapeutic治疗
Efforts
• Rare events (and clones) can dominate the
dynamics 动力of tumor mutation and growth
• There are many genetic and phenotypic表型
的 differences between tumors in different
individuals
• Therapeutic resistance对治疗剂的抗药性
commonly develops, via different routes
Rx
Therapies Select for
Resistance Mutations
• With 109–1012 cells in a neoplasm 瘤and 104+ mutations,
the presence of a resistance mutation is likely
•
Imatinib甲磺酸伊马替尼 (Gleevec) resistance:
– Point mutations in the kinase 激酶domain of BCR-ABL – Gorre & Sawyers.
Curr. Opin. Hematol. 9:303-7 (2002)
– Mutation present before therapy – Roche-Lestienne & Preudhomme. Sem.
Hematol. 40:80-2 (2003)
•
Gefitinib吉非替尼 resistance:
– EGFR mutation – Kobayashi et al. NEJM 352:786-92 (2005)
– MET amplification – Engelman et al. Science 316:1039-43 (2007)
•
5-fluorouracil五氟脲嘧啶 resistance: TYMS amplification –
- Wang et al. PNAS 101:3089–3094 (2004)
We are not winning the
‘War on Cancer’
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
(1) Over 200$ billion spent
(2) Combination chemotherapy
can defeat a few cancers (leukemia白血病,
lymphoma,testicular cancer)
(3) Most cancers are not curable, if
found too late; success of new drugs,
other treatments is measured in
terms of delaying death by a few months
WHY ARE WE LOSING?
WHAT CAN BE DONE DIFFERENTLY?
PUT EVOLUTIONARY BIOLOGY TO WORK